Moderate-severe Alzheimer's Disease Research Articles

Alzheimer disease: sleep, orexin and cognitive decline

Introduction In Alzheimer’s disease (AD) several networks including regions regulating the sleep-wake rhythm are altered. Orexin-A is an hypothalamic neuropeptide contributing to the regulation of the sleep-wake cycle. The aim of our study was to investigate the possible involvement of the orexinergic system in the AD neurodegenerative processes and its relationship with sleep impairment. Materials and methods We included 48 consecutive untreated AD patients and 29 healthy controls. Based on MMSE, AD patients were divided in 2 groups: mild AD (MMSE ⩾ 21; 21 subjects) and moderate-severe AD (MMSE 21; 27 subjects). We quantified orexin CSF levels in AD patients and controls, and examined potential links to the established AD markers CSF levels, as tau, phospho-tau (ptau), and beta-amyloid1–42 (A β 1–42). Moreover, AD patients underwent a full nocturnal polysomnography (PSG). Finally, CSF results were correlated with sleep structure parameters and MMSE. Results Regarding CSF data, control subjects showed orexin CSF levels not significantly different with AD patients as well as with mild AD subjects. However, moderate-severe AD patients showed increased orexin CSF levels in respect to both mild AD patients and controls. Regarding PSG parameters, moderate–severe AD patients, compared to mild AD subjects, showed a significant reduction in sleep efficiency (SE) and a significant increase in wakefulness after sleep onset (WASO) and in REM latency. Moreover, in AD patients the orexin CSF levels were negatively correlated with REM sleep, slow wave sleep (SWS) and SE, whereas were positively correlated with WASO and sleep latency. Furthermore, it appeared to exist a positive correlation between the increase of orexin and tau CSF levels in AD patients. A β 1–42 CSF levels were negatively correlated with WASO whereas were positively correlated with REM sleep. Tau CSF levels were negatively correlated with SWS. The decrease of MMSE correlated with the impairment of SE and REM sleep and the increase of WASO. Conclusion Our study shows that in AD cognitive decline is linked to a parallel sleep deterioration, which appears to be related to an increase of the CSF orexin levels. In conclusion, our results demonstrate that the orexinergic system is not impaired in AD, but its output and function appears to be overexpressed along the progression of neurodegenerative processes, possibly due to an unbalance of the neurotransmitters networks regulating the wake-sleep cycle towards the systems promoting wakefulness. Acknowledgements We are grateful to Ms. Alessandra Nitti for technical support, Dr. Francesca Izzi for acquisition of data, Prof. Nicola Biagio Mercuri for study supervision and Prof. Giuseppe Sancesario and Dr. Alessandro Martorana for acquisition of data and study supervision.

Efficacy of Memantine, Donepezil, or Their Association in Moderate‐Severe Alzheimer’s Disease: A Review of Clinical Trials

Background. Acetylcholinesterase (AChE)/cholinesterase (ChE) inhibitors (Is) and memantine are licensed for symptomatic treatment of mild-moderate and moderate-severe forms of Alzheimer's disease (AD), respectively. High doses of the AChE-I donepezil were licensed in the USA for moderate-severe AD, and the association AChE/ChE-Is plus memantine was proposed for AD at this stage. Objectives. This paper has reviewed evidence from clinical trials of the effectiveness of memantine, donepezil, or the two drugs in association in managing moderate-severe AD. Method. Double-blind, placebo-controlled randomized trials (RCTs) using memantine or donepezil alone or in association versus placebo in moderate-severe AD were reviewed. Analysis done in January 2013 considered the years 2007–2012. Results and Conclusion. Only 83 of the 941 papers selected were considered relevant, and only 13 met the criterion of “adequacy and representativeness.” Memantine and donepezil lead to improvements in moderate-to-severe AD and the choice between the compounds should be based on their contraindications more than on disease severity. No evidence was found of advantages of the association of memantine-donepezil. The heterogeneity of conditions explored by RCTs, the relatively short time of observation (24–52 weeks), and the different cognitive assessment tools used did not allow comparing properly different trials.

Benefits of combined cholinesterase inhibitor and memantine treatment in moderate–severe Alzheimer's disease

BackgroundClinical studies and post hoc analyses have investigated the use of combination therapy for the treatment of Alzheimer's disease (AD). We review the evidence for the short- and long-term efficacy of combination therapy in AD. MethodsThe review is based on a search of the PubMed database to identify relevant articles concerning combination treatment with memantine and cholinesterase inhibitors (ChEIs). ResultsIn patients with moderate-to-severe AD, combination treatment with the N-methyl-d-aspartate receptor antagonist memantine and the ChEI donepezil has produced significant benefits in cognition, function, behavior, global outcome, and care dependency, compared with donepezil treatment alone. Data from long-term observational studies support these findings. Compared with ChEI monotherapy, combination treatment slowed cognitive and functional decline (a 4-year sustained effect that appeared to increase over time) and reduced the risk of nursing home admission. Preclinically, the combination of N-methyl-d-aspartate receptor modulation and acetylcholinesterase inhibition has been shown to act synergistically, which may explain the observed clinical effects of combination treatment. ConclusionTreatment with memantine/ChEI combination therapy in moderate-to-severe AD produces consistent benefits that appear to increase over time, and that are beyond those of ChEI treatment alone.

Ghrelin and leptin secretion in patients with moderate Alzheimer's disease.

Weight loss is a characteristic finding of patients with Alzheimer's disease (AD). It seems that precedes cognitive impairment by some years, but the underlying causes are not fully understood. Ghrelin and leptin are involved in energy homeostasis, and may be implicated in weight losing observed in these patients. To examine the potential relationship between ghrelin and leptin levels and weight loss in patients with AD. The study included 27 patients (10 men and 17 women) with AD of moderate severity, and 23 controls (10 males and 13 females), matched for age and BMI. Body fat and lean mass content were assessed using a portable apparatus. Cognitive function was assessed with the Mini-Mental State Examination. Basal serum samples for the measurement of leptin, ghrelin, insulin and glucose were obtained, and serum ghrelin, insulin and glucose were measured after a 75-gr glucose load in both groups. Patients with Alzheimer Disease (AD) have lower lean mass content compared to controls. Basal ghrelin and leptin is similar in patients with AD and controls. The area-under-the-curve for ghrelin (AUC) is lower in male patients with AD compared to control males, while no difference was observed between females AD and controls. Male patients with AD, in contrast with female patients, fail to maintain a normal energy homeostasis even in the early stages of the disease, as shown by the decreased lean mass content in males AD compared to controls. Disruption of the normal compensatory modulation of ghrelin secretion might contribute to the metabolic changes observed in male patients with AD.

Managing Agitated Behaviour in People with Alzheimer's Disease: The Role of Live Music

Background: Agitation due to Alzheimer's disease (AD) presents a challenge to occupational therapists working in the older people care sector. Recently, background music and music therapy have emerged as promising tools in the management of agitation in AD. This exploratory study investigated whether live music could reduce agitated behaviour in people with AD. Method: A quasi-experimental one-group repeated measures design investigated the effect of a live, one-to-one, musical violin intervention on agitated behaviour in people with moderate-severe AD in a residential care facility. Seven participants received the musical intervention on three occasions. Participants were video recorded before, during and after each session. Behaviour was assessed by the investigator and a blinded assessor, using an investigator-modified Cohen-Mansfield Agitation Inventory. Thirty agitated behaviours were examined. Data were analysed using the Friedman test. Results: This intervention reduced agitated behaviour among participants. Significant reductions in pacing/aimless wandering (p = 0.023), performing repetitious mannerisms (p = 0.036) and general restlessness (p = 0.007) were observed. The total number of agitated behaviours decreased significantly (median 5 [range 2–8] behaviours before the intervention to 1 [range 0–4] during and 1 [range 0–5] after the intervention [p = 0.005]). Conclusion: Live music may be an effective strategy to reduce short-term agitated behaviour among people with AD.

Prevalence of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Alzheimers Disease, and its Relationship with Cognitive Impairment

The study aimed to describe the prevalence of Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD), amnestic mild cognitive impairment (MCI) and controls using the 12-item Neuropsychiatric Inventory (NPI) and to analyze the relationships between neuropsychiatric symptoms with specific neuropsychological tests. We prospectively studied 485 patients from the Memory Unit in Cruces Hospital (Spain), 344 met the criteria of NINCDS-ADRDA for probable AD (99 were classified as mild and 245 as moderate-severe), 91 for MCI and 50 were controls. Mini-mental State Examination (MMSE) and CDR (Clinical Dementia Rating) were used to evaluate global cognitive function and to classify the severity of cognitive impairment. The neuropsychological test battery included memory test, verbal fluency, visuoespatial skills and daily living scales. The 12-items Neuropsychiatric Inventory (NPI) version was used to assess neuropsychiatric symptoms. All patients underwent a neuroimaging study (CT scan and/or MRI). Patients were not treated with antidementia or psychotropic drugs. Apathy and depression were more prevalent NPS in moderate-severe AD (78.4% and 44.1%, respectively), mild AD (64.6% and 41.4%, respectively) and MCI (50.5% and 33%, respectively) patients than in controls (6% and 8%, respectively). The prevalence and the mean scores of all symptoms increased along the severity of the disease, except for sleep and appetite disorders. In patients with mild AD a relationship was found between the presence of NPS and RDRS-2 scale (p = 0.003); and between NPS and RDRS-2 (p = 0.029) and SS-IQCODE scales (p = 0.039) in moderate-severe patients. NPS were more prevalent in AD and MCI patients than in controls. In AD and MCI patients apathy and depression were the most prevalent NPS. The prevalence and the mean scores of all symptoms gradually increased along the severity of the disease, except for sleep and appetite disorders. We have no found a relationship between neuropsycological test and the presence of NPS, but in patients with mild and moderate-severe AD there is a relationship with daily living scales.

Microstructural Diffusion Changes are Independent of Macrostructural Volume Loss in Moderate to Severe Alzheimer's Disease

Although it is established that Alzheimer's disease (AD) leads to cerebral macrostructural atrophy, microstructural diffusion changes have also been observed, but it is not yet known whether these changes offer unique information about the disease pathology. Thus, a multi-modal imaging study was conducted to determine the independent contribution of each modality in moderate to severe AD. Seventeen patients with moderate-severe AD and 13 healthy volunteers underwent diffusion-weighted and T1-weighted MR scanning. Images were processed to obtain measures of macrostructural atrophy (gray and white matter volumes) and microstructural damage (fractional anisotropy and mean diffusivity). Microstructural diffusion changes independent of macrostructural loss were investigated using an ANCOVA where macrostructural maps were used as voxel-wise covariates. The reverse ANCOVA model was also assessed, where macrostructural loss was the dependent variable and microstructural diffusion tensor imaging maps were the imaging covariates. Diffusion differences between patients and controls were observed after controlling for volumetric differences in medial temporal, retrosplenial regions, anterior commissure, corona radiata, internal capsule, thalamus, corticopontine tracts, cerebral peduncle, striatum, and precentral gyrus. Independent volumetric differences were observed in the entorhinal cortex, inferior temporal lobe, posterior cingulate cortex, splenium and cerebellum. While it is well known that AD is associated with pronounced volumetric change, this study suggests that measures of microstructure provide unique information not obtainable with volumetric mapping in regions known to be pivotal in AD and in those thought to be spared. As such this work provides great understanding of the topography of pathological changes in AD that can be captured with imaging.

Validez de la escala MNA como factor de riesgo nutricional en pacientes geriátricos institucionalizados con deterioro cognitivo moderado y severo

Introduction: comprehensive geriatric assessment includes examination of the nutritional status given the high prevalence of hyponutrition in this kind of patients, particularly in patients with associated cognitive impair- ment. Scales for screening the nutritional status include questions on self-perception difficult to answer by demented elder patients. Objective: To study the specificity, the positive predic- tive value, and the sensitivity of the MNA scale to detect malnutrition in patients diagnosed with Alzheimer's dis- ease with advanced cognitive impairment. Material and methods: a population-based descriptive study with a sample of 52 patients older than 70 years, institutionalized, and with moderate-severe Alzheimer's disease was designed. The sensitivity, specificity, and pos- itive predictive value of MNA scale were studied regard- ing the parameters on malnutrition of the American Institute of Nutrition (AIN). Results: the sensitivity, specificity, and positive predic- tive values were 60%, 94.7%, and 93.8%, respectively. There was a significant correlation (p < 0.001) between the score obtained with the MNA Scale and the Tinneti's Risk of Fall Scale (r = 0.577), the Barthel's function (r = 0.742), the MCT cognitive assessment (r = 0.651), and cre- atinine levels (r = 0.402). More than 50% of the sample presented at least one malnutrition parameter altered. Conclusions: the MNA Scale presents lower sensitivity and specificity in these patients. Designing a nutritional assessment scale without subjective evaluations and only with objective parameters might improve its efficiency in institutionalized elderly patients with moderate-severe cognitive impairment. (Nutr Hosp. 2009;24:724-731) DOI:10.3305/nh.2009.24.6.4571

Rapid cognitive decline in Alzheimer’s disease. Consensus paper

The rate of cognitive decline in Alzheimer's disease (AD) varies considerably between individuals, with some subjects showing substantial deterioration and others showing little or no change over the course of the disease. These wide variations support the relatively new concept of Rapid Cognitive Decline (RCD). Patients with an accelerated rate of cognitive decline have showed to present a worse evolution in terms of mortality, loss of autonomy and institutionalisation. The conclusions from RCD studies conducted in the past years remain very heterogeneous and sometimes contradictory. This is possibly due to methodological differences, mainly the different "a priori" definitions of RCD used to identify rapid decliners. Consequently of this, there is considerable variation in reported frequency of patients with RCD which may vary from 9.5% to 54%. The lack of both consensus definition and consensual clinical assessment tools is one of the major barriers for establishing an appropriated management of rapid decliners in clinical practice. Presently, management of rapid decliners in AD remains to be a challenge waiting to better know predictive factors of a RCD. To date no specific guidelines exist to follow-up or to treat patients with this condition. This consensus paper proposes the loss of 3 points or greater in Mini-Mental State Examination (MMSE) during six months as an empirical definition of rapid cognitive decline to be used in routine medical practice and to be relevant for clinical-decision making in patients with mild to moderately-severe AD.

Treatment Effect Size of Memantine Therapy in Alzheimer Disease and Vascular Dementia

The purpose of this paper is to assess the clinical relevance of the significant results reported in clinical trials of memantine therapy for Alzheimer disease (AD) and vascular dementia. We sought to understand what clinically detectable changes would be evident to the patient with dementia, their caregivers, and the treating physician during a trial of memantine therapy. A literature search was performed on MedLine, PsycInfo, and the Cochrane database. The statistically significant findings from the memantine literature were reviewed using treatment effect size as a measure of clinical meaningfulness. There have been 3 phase 2 studies of memantine in dementia, and 6 phase 3 studies published as of August 1, 2005. Of the 6 published phase 3 trials of memantine in dementia; 2 were in mild-moderate vascular dementia, 1 in mild-moderate AD, 2 in moderate-severe AD, and 1 in severe dementia (both AD and vascular dementia). The most convincing evidence of a clinically meaningful treatment effect of memantine therapy is in the moderate-severe AD patient population. Cognition, as measured by the Severe Impairment Battery, had an effect size of 0.32 and 0.49 in the 2 published trials, indicating a small-to-medium effect of the medication. Global, functional, and behavioral scales also showed a small-to-medium response to memantine.

A systematic review of the clinical effectiveness of donepezil, rivastigmine and galantamine on cognition, quality of life and adverse events in Alzheimer's disease

The use of cholinesterase inhibitors for Alzheimer's disease (AD) is currently being appraised by the National Institute for Clinical Evidence (NICE). This article provides the latest evidence that NICE will be using as part of this appraisal process. To provide a systematic review of the best quality evidence of the effects of donepezil, rivastigmine and galantamine on cognition, quality of life and adverse events in people with mild to moderately-severe AD. Electronic databases were searched, references of all retrieved articles were checked, and experts were contacted for advice, peer review and to identify additional references. Randomised controlled trials (RCTs) were included if they fulfilled pre-specified criteria. Data were synthesised through a narrative review. Twenty-six RCTs that compared any one of the cholinesterase inhibitors with either a control group or with another cholinesterase inhibitor were included. The quality of reporting and methodology was varied. Treatment with donepezil, rivastigmine or galantamine resulted in significantly better cognitive performance using the ADAS-cog scale when compared with placebo. These findings were generally supported using the MMSE scale. Results from head to head comparisons were limited by the low number of studies and the study quality; generally showing no robust support for any one drug. Few studies evaluated quality of life. Adverse events were generally related to the gastrointestinal system, with a tendency for these to be more common in the treatment arms. The cholinesterase inhibitors donepezil, rivastigmine, and galantamine can delay cognitive impairment in patients with mild to moderately-severe AD for at least 6 months duration.

Rivastigmine and donepezil treatment in moderate to moderately-severe Alzheimer's disease over a 2-year period

ABSTRACTObjectives: Randomised controlled trials that directly compare cholinesterase inhibitors for the treatment of Alzheimer's disease have been characterised by significant methodological limitations. As a consequence, they have failed to establish whether there are differences between agents in this class. To help address this question, a double-blind, randomised, controlled, multicentre trial was designed to evaluate the efficacy and tolerability of cholinesterase inhibitor treatment in patients with moderate to moderately-severe Alzheimer's disease over a 2-year period.Methods: Patients were randomly assigned to rivastigmine 3–12 mg/day or donepezil 5–10 mg/day. Efficacy measures comprised assessments of cognition, activities of daily living, global functioning and behavioural symptoms. Safety and tolerability assessments included adverse events and measurement of vital signs.Results: In total, 994 patients received cholinesterase inhibitor treatment (rivastigmine, n = 495; donepezil, n = 499), and 57.9% of patients completed the study. The most frequent reason for premature discontinuation in both treatment groups was adverse events, primarily gastrointestinal. Adverse events were more frequent in the rivastigmine group during the titration phase, but similar in the maintenance phase. Serious adverse events were reported by 31.7% of rivastigmine- and 32.5% of donepezil-treated patients, respectively. Rivastigmine and donepezil had similar effects on measures of cognition and behaviour, but rivastigmine showed a statistically significant advantage on measures of activities of daily living and global functioning in the ITT–LOCF population. However, this was not maintained in the non-ITT–LOCF populations. In secondary sub-group analyses, AD patients who had genotypes that encoded for full expression of the butyrylcholinesterase enzyme (BuChE wt/wt; n = 226/340), who were < 75 years of age (n = 362/994) or who had symptoms suggestive of concomitant Lewy body disease (n = 49/994) showed significantly greater benefits from rivastigmine treatment.Conclusions: Cholinesterase inhibitor treatment may offer continued therapeutic benefit for up to 2 years in patients with moderate AD. Although both drugs performed similarly on cognition and behaviour, rivastigmine may provide greater benefit in activities of daily living and global functioning.

Functional, Cognitive and Behavioral Effects of Donepezil in Patients with Moderate Alzheimer's Disease

SummaryObjective: To investigate the efficacy and safety of donepezil in a subgroup of patients with Alzheimer's disease (AD) of moderate severity from a previous trial.Methods: Two hundred and seven patients with moderate AD (standardized Mini-Mental State Examination [sMMSE] score 10-17) were randomized to treatment in this 24-week, double-blind, placebo-controlled trial. Patients received either donepezil, 5mg/day for the first 28 days and 10mg/day thereafter according to the clinician's judgement (n = 102), or placebo (n = 105). The primary outcome measure was the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC-plus) at week 24 using a last observation carried forward (LOCF) analysis.Results: Baseline patient demographics were similar between treatment groups. Mean age was 74.3 years (range 48–92). Least-squares (LS) mean sMMSE scores at baseline were 13.6 ± 0.3 for the donepezil group and 13.9 ± 0.3 for the placebo group. LS meanCIBIC-plus scores for donepezil-treated patients were improved from, or close to, baseline severity at all visits, and were significantly different from placebo at weeks 8,12,18, and 24 (week 24 LOCF mean difference = 0.53, p = 0.0003). LS mean change from baseline scores on the sMMSE and Severe Impairment Battery (SIB) for the donepezil group improved throughout the study, and were significantly different from placebo at each visit for the sMMSE (week 24 LOCF mean difference = 2.06, p = 0.0002) and from week 8 for the SIB (week 24 LOCF mean difference = −4.44, p = 0.0026). LS mean change scores on the Disability Assessment for Dementia remained at or above baseline levels throughout the study for the donepezil group, while the placebo group showed a steady decline; treatment differences were significant at each visit (week 24 LOCF mean difference = −9.25, p < 0.0001). LS mean change scores on the Neuropsychiatric Inventory 12-item total improved throughout the study for the donepezil group and were significantlydifferent from placebo at weeks 4 and 24 (week 24 LOCF mean difference = 5.92, p = 0.0022). Eighty-one per cent of donepezil-treated and 89% of placebo-treated patients completed the trial, with 9% and 5%, respectively, discontinuing due to adverse events (AEs). Eighty-two per cent of donepezil-treated and 80% of placebo-treated patients experienced AEs, the majority of which were rated mild in severity and, in general, were similar between treatment groups.Conclusion:The significant treatment responses observed with donepezil in these patients reinforce the findings from earlier studies that show donepezil to have important benefits, compared with placebo, across functional, cognitive, and behavioral symptoms, with good tolerability, in patients with AD of moderate severity.

IL-2 and IL-6 secretion in dementia: correlation with type and severity of disease

The production of interleukin-2 (IL-2) and interleukin-6 (IL-6) by peripheral blood mononuclear cells (MNC) was assessed in patients with Alzheimer's disease (AD) who were subdivided into two groups — mild and moderately-severe — according to the severity of the disease, probable vascular dementia (VaD) patients and elderly control subjects. No differences in IL-2 secretion were found between mild AD patients and controls. However, there was a significant increase in IL-2 production both in the moderately-severe AD group and in the VaD group. IL-6 levels in AD patients of both groups were similar and significantly higher than those of VaD and controls. Our results suggest that increased levels of IL-2-production correlate with severity of the dementia, whereas increased levels of IL-6 production seem to be related to AD and thus may play a role in AD pathogenesis.

Semantic memory in Alzheimer's disease: an analysis of category fluency.

In order to study the strategies of access to semantic knowledge and the status of semantic representation, we analyzed the performance in a semantic fluency task (Animal naming) of 70 patients with probable Alzheimer's disease (AD), including 40 mild AD patients and 30 moderate-severe AD patients, and 35 matched elderly normal control subjects. The total amount of words produced, their lexical frequency, the number and type of errors, as well as the presence and the type of clusters of related animal names were recorded. AD patients produced less animal exemplars than controls. In addition to a lower total number of clusters, the AD patients showed a strong limitation in clusters' selection, producing a limited number of different clusters. While normal subjects produced several different clusters, only farm animals were clustered by AD patients. When the total amount of words was considered, the mean lexical frequency was higher in the AD group. On the other hand, the words produced within clusters were comparable to terms of lexical frequency and number. These data confirm the impairment of AD patients in category fluency tasks, and suggest a degradation of semantic knowledge as the most likely underlying mechanism.

Sleep Disturbances in Patients With Mild-Stage Alzheimer's Disease

We examined the ability of sleep/wake measures to discriminate 45 control subjects from 44 mild Alzheimer's disease (AD) patients. Sleep fragmentation was observed as indicated by significant increases in time awake (37-52%) and number of awakenings (31-36%) during the night as compared to controls. Further, slow wave sleep (SWS) was significantly reduced (22%) in AD patients relative to controls. These findings are consistent with our earlier observations of increased wakefulness and decreased SWS in mild-moderate, moderate-severe, and severe stage AD patients. However, when we used these sleep/wake stage measures in discriminant analyses to classify the current AD subjects vs control subjects, the analyses failed to confirm our earlier high classification rate (90%). The present groups were discriminated at overall classification rates of only 63-67%. We conclude that while sleep/wake patterns are significantly disturbed in AD, this phenomenon is not diagnostically useful for discrimination of mild stage AD.